PROJECT SUMMARY/ABSTRACT Finding a resolving cure for Alzheimer?s Disease (AD), is an urgent critical need. There is ample consensus that successful treatments should target early pathological events in AD. Among these, synaptic dysfunction induced by oligomers of both A? and tau is recognized as one of the earliest key driving events in AD and thus an attractive treatment target, but an effective strategy is still missing. Our long-term goal is to help develop therapeutically useful approaches to increase synaptic resilience to A? and tau oligomers for the clinical treatment of AD patients. With this goal in mind, we recently reported that exosomes specifically released by hippocampal neural stem cells (NSC-exo) render CNS synapses resilient to the disruptive impact of A? oligomers via selected micro RNA (miRNA) cargoes, a mechanism likely at play in the human brain as suggested by reports of aged individuals with high numbers of NSC and synapses resilient to A? oligomers who remain cognitively intact despite the CNS presence of extensive AD neuropathology. Whether such mechanism of resilience is also effective against synaptic disruption brought about by tau oligomers- a recognized major player in the onset and clinical progression of AD- remain to be established. Thus, the overall objective in this application, is to evaluate the link between NSC (and their released exosomes) and increased synaptic resilience to the toxic actions of tau oligomers as a function of aging, the strongest AD risk factor. Based of rigorous previous literature reports and compelling preliminary results, our central hypothesis is that NSC-exo, via delivering unique miRNA cargoes, render synapses resistant to toxic tau oligomers and that such protective mechanism fails during aging owing to the well-documented age-related loss of NSC, leaving the aged brain more vulnerable to the AD toxic amyloids (and therefore more at risk of developing clinically manifest AD). The rationale for this project is that a determination of the preclinical therapeutic efficacy and associated mechanisms of NSC-exo (and their miRNA cargoes) as a function of aging is likely to offer a strong scientific framework whereby a new strategy centered on promoting synaptic resilience to AD pathological oligomers could be developed. To obtain the overall objective, we will pursue three specific aims that will evaluate the efficacy of NSC-exo in promoting synaptic resilience to Tau oligomers (Aim 1), determine the invoved miRNA cargoes and their impact on key synaptic proteins (Aim 2) and evaluate the impact of aging on such protective mechanisms as a function of decreasing numbers of resident NSC and their released exosomes (Aim 3). At the completion of the proposed studies, it is our expectation that we will have documented a previously unappreciated phenomenon of synaptic resistance to toxic oligomers mediated by NSC-exo and their miRNA cargo that fails during aging. This discovery will illustrate targets for the development of an innovative treatment concept for AD centered on sustaining synaptic resistance to toxic oligomers in an aging environment, a strategy expected to be effective in humans as suggested by the existence of aged resilient subjects with high NSC numbers and synapses that reject oligomers.